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Neurofibromin pathway modulators

a neurofibromatosis and pathway technology, applied in the field of neurofibromatosis treatment methods, can solve the problems of poor 5-year survival rate, precocious puberty or other neurological abnormalities, and inability to effectively treat the diseas

Active Publication Date: 2009-08-20
WASHINGTON UNIV IN SAINT LOUIS
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Optic pathway tumors can lead to blindness or invade into nearby brain regions or the subarachnoid space to result in precocious puberty or other neurological abnormalities.
However, 5-year survival rates are dismal, and no effective chemotherapy regimens are available.
In addition, mean survival appears to be worse in NF1 subjects with MPNST than for those in the general population.

Method used

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Examples

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example 1

NF1-Deficient Cells and Tumors Exhibit High Levels of mTOR Pathway Activation

[0095]Two-dimensional gel proteomic profiling was used to identify signaling pathways deregulated by neurofibromin 1 inactivation in astrocytes. These experiments demonstrated increased expression of numerous members of the ribosomal synthesis pathway, including NPM, a key regulator of ribosome maturation and export (FIG. 1). Since ribosomal synthesis is modulated by the mTOR / S6K pathway, the activation status of select members of the mTOR pathway was analyzed, including S6K1, S6, and 4EP-B1 using activation-specific antibodies (FIG. 2). Increased activation of S6K1 and S6, but not 4E-BP1, in neurofibromin 1 deficient astrocytes was observed, suggesting that the S6K1 / S6 arm of the mTOR pathway was hyperactivated. To provide an in vivo correlate for these in vitro findings, mTOR pathway activation was examined in optic glioma arising in neurofibromin 1 genetically-engineered mice (GEM) and in human NF1-assoc...

example 2

Rapamycin Inhibition of mTOR Pathway Activation Blocks Neurofibromin 1 Deficient Cell Growth

[0096]Pharmacologic inhibitors that block mTOR activation include rapamycin and related synthetic derivatives (e.g., RAD001, CCI-779). First, it was demonstrated that rapamycin inhibits mTOR pathway activation in neurofibromin 1 deficient astrocytes. In these experiments, complete inhibition of S6 activity was observed using phospho-specific antibodies after treatment with 1 nM rapamycin (FIG. 4).

[0097]Second, this low dose of rapamycin was shown to completely inhibit the proliferative advantage of neurofibromin 1− / − astrocytes in vitro without any effect on the growth of wild-type (neurofibromin 1+ / +) astrocytes (FIG. 5). Finally, a human NF1-associated MPNST cell line (ST88-14) was engineered with a luciferase expression construct to allow for in vivo visualization and in vitro rapid analyses of cell growth (FIG. 6). Using the ST88-14-luc cell line, treatment with rapamycin effectively inhi...

example 3

Neurofibromin Regulation of mTOR Signaling

[0098]Evidence exists for direct activation of mTOR signaling by Akt as well as indirect activation of mTOR by Akt through the tuberous sclerosis complex (TSC) / Rheb pathway. Studies have shown that the mTOR activation resulting from neurofibromin loss in astrocytes can be reversed by restoring NF1-GAP activity (NF1 GRD), blocking K-RAS activity (K-RASN17), or inhibiting PI-3K activation of Akt. In these experiments, replacement of the GAP domain in neurofibromin 1 deficient astrocytes reduced S6 activation levels to normal (FIG. 7a). Similarly, the increased S6 activation in neurofibromin 1 deficient astrocytes was reversed upon the introduction of a dominant inhibitory K-RAS molecule (FIG. 7b) or inhibition of PI-3K using the LY294002 compound (FIG. 4b). Collectively, these results suggest that neurofibromin regulates mTOR signaling through RAS / Akt.

[0099]While one report found that neurofibromin 1 regulation of mTOR signaling involved the T...

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Abstract

The present invention encompasses methods for treating neurofibromatosis and methods for screening for modulators of the neurofibromin pathway.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the priority of U.S. provisional application No. 60 / 987,156, filed Nov. 12, 2007, which is hereby incorporated by reference in its entirety.GOVERNMENTAL RIGHTS[0002]This invention was made in part with Government support under Grant Number DAMD-17-03-1-0215 awarded by The Department of Defense and Grant Number U01-CA84314 awarded by the National Cancer Institute. The Government may have certain rights in this invention.FIELD OF THE INVENTION[0003]The present invention relates to methods for treating neurofibromatosis and to methods for screening for modulators of the neurofibromin pathway.BACKGROUND OF THE INVENTION[0004]NF1 is a common autosomal dominant disorder that affects approximately 1:3000 people worldwide (over 100,000 individuals in the United States alone) and predisposes to the development of both benign and malignant tumors, including optic glioma and malignant peripheral nerve sheath tumor (MPNST). Op...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/68A61K31/436C12N5/10
CPCA61K31/436A61K45/06C12Q1/6883G01N33/5011C12Q2600/136C12Q2600/158C12Q2600/156C12Q2600/106G01N33/5023A61K2300/00
Inventor GUTMANN, DAVIDWEBER, JASON
Owner WASHINGTON UNIV IN SAINT LOUIS
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